1. Field of the Invention
The present invention relates, in general, to a human CRIPTO-related gene. In particular, the present invention relates to a DNA segment encoding a human CRIPTO-related gene; polypeptides encoded by the DNA segment; recombinant DNA molecules containing the DNA segment; cells containing the recombinant DNA molecule; a method of producing a human CRIPTO-related polypeptide; a DNA segment encoding a genomic clone of the human CRIPTO gene (CR-1); antibodies specific to CR-3; and a method of measuring the amount of CR-3 in a sample.
2. Background Information
Polypeptide growth factors play a role in stimulating cell proliferation. Their genes are expressed in the developing embryo, in normal adult tissues and in tumor cells (for review see Devel, T. F., Ann., Rev. Cell Biol. (1987) 3:443-492; Sporn, M. B. et al., Nature (1987) 332:217-219; Whitman, M. et al., Ann. Rev. Biol. (1989) 5:93-117). Characterization of these factors and sequencing of their genes have permitted their grouping into a relatively small number of families on the basis of sequence similarities (Mercola, M. et al., Development (1988) 108:451-460). One of these is the epidermal growth factor (EGF) family. EGF (Savage, C. R. et al., J. Biol. Chem. (1972) 247:7612-7621), transforming growth factor .alpha. (TGF.alpha.) (Derynck, R. et al., Cell (1984) 38:287-297) and amphiregulin (AR) (Plowman, G. D. et al., Mol. Cell Biol., (1990) 10:1969-1981) share structural similarities including the conservation of six cysteines of the "EGF motif", which in EGF are involved in three disulfide bonds defining the tertiary structure. The presence of "EGF motif" also in developmental genes, such as Notch in Drosophila (Kidd, S. et al., Mol. Cell. Biol. (1986) 6:3094-3108) and lin-12 in C. elegans (Greenwald, I., Cell (1985) 43:583-590), may imply a novel role for the growth factors of the "EGF family." It has been suggested that they may exert their action on the cell surface during development to mediate cell-cell interactions by recognizing a complementary receptor on another cell.
Previously, the isolation of a human cDNA, referred to as CRIPTO (CR-1)(Ciccodicola, A. et al., EMBO J. (1989) 8:1987-1991), encoding a protein of 188 amino acids was described. The central portion of this protein shares structural similarities with the human TGF.alpha.(Derynck, R. et al., Cell (1984) 38:287-297), human AR (Plowman, G. D. et al., Mol. Cell Biol,, (1990) 10:1969-1981) and human EGF (Savage, C. R. et al., J. Biol. Chem. (1972) 247:7612-7621). Northern blot analysis of a wide variety of tumor and normal cell lines and tissues (e.g., choriocarcinoma, fibroblast, neuroblastoma, HeLa, placenta and testis) has shown that CRIPTO transcripts are detected only in undifferentiated human NTERA-2 clone D1 (NT2/N1) and mouse (F9) teratocarcinoma cells and these disappear after inducing the cells to differentiate with retinoic acid treatment (Ciccodicola, A. et al., EMBO J. (1989) 8:1987-1991).